This Program-Project grant is concerned primarily with various aspects of the biochemistry, biology and pathology of connective tissues. Additionally, certain projects relate to the glycosphingolipids and glycoproteins and their disturbed metabolism in certain human genetic diseases. The mechanisms and control of biosynthesis of chondroitin sulfate proteoglycan in cartilage are being investigated by purification of the involved glycosyltransferases and study of their interactions and control of their synthesis. The mechanism of differentiation of chick embryo limb bud mesenchyme to cartilage is being investigated with a view of determining the mechanisms of derepression of the genes responsible for the secific phenotypic molecules of cartilage. This study includes an attempt to elucidate the mechanism by which bromodoxyuridine irreversibly inhibits cartilage differentiation. The heritable human diseases which involve aberrations of metabolism of complex carbohydrates (the mucopolysaccharidoses, glycosphingolipidoses and glycoproteinoses) are subjects of investigations to establish their enzymic bases and pathogenesis. The studies are coupled with investigations on cultured cells of the central nervous system aimed at clarifying the role of glycosphingolipids in the central nervous system.